[1231]iodobenzovesamicol (IBVM), developed previously in our department at the University of Michigan, has been used for studying the vesicular acetylcholine transporter (VAChT) binding site in vivo using single photon tomography (SPECT). While this tracer has been used successfully to study VAChT in normal controls and neurological patients, it has inherent limitations. First and most importantly, the statistical quality of the data are limited by the fact that 1231is a single-photon emitter, not a positron emitter. Second, the acquisition and analysis protocols require either i) 3 to 4 hours of dynamic imaging following radioligand injection and arterial blood sampling including metabolite analysis, a long procedure difficult for many patients to tolerate, or ii) static imaging on the 2nd day following injection, -2 half-lives after injection thus reducing image statistics further in addition to requiring a second visit to the department. A positron-labeled radioligand would avoid these limitations, providing the possibility of a much higher quality study in terms of count statistics and the ability to complete the scan in a timely fashion within the same day. In this application we propose to develop, implement and validate a method for imaging VAChT density using the positron-labeled radiotracer, [18F]fluoroethoxybenzovesamicol (FEOBV), a related tracer also developed previously in our department at the University of Michigan. We will to fully characterize the radioligand [18F]FEOBV, optimize its radiosynthesis, evaluate its pharmacokinetics in rodent and primate brain, and perform clinical evaluations in both normal control and patient groups. A brief outline of the project is as follows: R21 (Year 1): Cold chemical syntheses: synthesize and fully characterize both unlabeled FEOBV and the precursor to the radioligand [18F]FEOBV. Optimization of radiochemical synthesis. FEOBV toxicity testing. R21 (Year 2): Initial animal studies (using microPET R4 scanner). Biodistribution and kinetics will be determined in rats. Begin preparation of IND for human use of FEOBV R21 (Year 3): Submit and obtain IND. Pharmacokinetic studies will be performed in primates using the microPET P4 scanner. Perform pharmacological studies for tracer and kinetic model validation R33 (Year 4): Clinical evaluations in normal controls and in patient groups (e.g. AD). R33 (Year 5): Conclude clinical evaluations in normal control and patient groups.